Both T cell and B cell immune responses to HCV are being investigated. T cell studies are continuing in an effort to identify both cytotoxic T cell and helper T cell epitopes. We are studying the proliferative and CTL responses of patients with chronic HCV infections to peptide antigens and antigens expessed by recombinant DNA systems. Using predicted HLA A2 motifs from the HCV polyprotein, we identified five additional epitopes, 3 in the core protein, 1 in NS4B and 1 in NS5B. Experimental genetic vaccines against HCV are being studied. BALB/c mice have been shown to develop antibody after injection with a plasmid that expresses HCV E2. We have extended these experiments to include the HCV core and E1 genes as well as E2. Inoculated mice exhibit both antibody and CTL responses to specific HCV antigens. Using human HLA A2 transgenic mice, we have investigated the ability of DNA vaccine to induce a human-like CTL responses. Mice were immunized with an HCV/core DNA vaccine and were shown to develope CTL responses to to the same epitopes recognized by A2 patients infected with HCV. These HLA-A2 transgenic mice have been shown to be protected from a challenge with a recombinant vaccinia virus that expresses HCV core. Chimpanzees have been inoculated with experimental vaccines designed to produce antibody and/or CTL responses. Therapeutic vaccines are being tested in carrier chimpanzees.